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Triple-negative breast cancers (TNBC) have enhanced migratory behaviour. Here, the authors perform a phenotypic imaging-based RNAi screen to identify several genes associated with regulation of migratory phenotypes and show that one of the regulators, PRPF4B, mediates metastasis in TNBC in mice.

This study shows how the links between somatic passenger mutations in tumors and normal cell transcriptomes can be used to infer cell-of-origin in lung adenocarcinoma.

Anna Lasorella, Raul Rabadan, Antonio Iavarone and colleagues report an integrated analysis of genomic alterations in glioblastoma. They identify and functionally validate several new driver events, including loss-of-function mutations in CTNND2 and recurrent EGFR fusions.

TRPA1 has been reported to contribute lung cancer adenocarcinoma (LUAD), but the mechanisms are unclear. Here the authors propose that TRPA1/FGFR2 interaction is functional in LUAD and show that astrocytes oppose brain metastasis by mediating the downregulation of TRPA1 through exosome-delivered miRNA-142-3p.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Whole-genome sequencing of 1,013 clonal haematopoietic colonies from myeloproliferative neoplasms of 12 individuals reveals haematopoietic phylogenies and indicates that driver mutations are acquired sequentially, starting early in life.

Projected impacts of climate change on malaria burden in Africa by 2050 highlight the urgent need for climate-resilient malaria control strategies and robust emergency response systems to safeguard progress towards malaria eradication.

The authors previously pinpointed OLAH (oleoyl-ACP-hydrolase) as a driver of life-threatening viral diseases. Here, the authors identify increased IL-18Rα expression on CD8⁺ T cells, which acquire a reduced cytotoxic signature, correlates with severe respiratory viral infection of influenza A virus, RSV and COVID-19.

Mitochondrial dysfunction in dopaminergic neurons is a pathological hallmark of Parkinson’s disease. Here, the authors find a conserved mechanism by which a single transcription factor controls mitochondrial health in dopaminergic neurons during the aging process.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.

Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

This study advances methods for benchmarking macromolecular complex predictions by introducing a scalable open-source framework used in recent community assessments to compare structures, interfaces and ligand interactions against experimental data.

Radiation reaction (RR) on particles in strong fields is the subject of intense experimental research, but previous efforts lacked statistical significance due to the extreme regimes required. Here, the authors report a 5σ observation of RR and obtain strong, quantitative evidence favouring quantum models over classical, using an all-optical setup where electrons are accelerated by a laser in a gas jet before colliding with a second, intense pulse.

Changes in ocean fronts could impact biological productivity and carbon exchange. By analysing satellite and reanalysis data, the authors identify areas with active frontal activity and rapid change in properties, as well as highlighting the correspondence with surface productivity and CO₂ uptake.

Analysis of hematopoietic stem cells from six individuals with sickle cell disease who had been treated with autologous gene therapy revealed positive selective pressure on cells containing mutations in genes associated with clonal hematopoiesis and hematological malignancies.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Eight decades of forest plot monitoring show a pervasive increase in tree mortality across Australia’s forest biomes driven by climate change, jeopardizing their role as enduring carbon sinks.

Most cancer genomics studies have focused on identifying the most important somatic mutations ('major drivers') that promote tumour growth. However, many cancer-associated mutations might instead have relatively weak tumour-promoting effects. This Opinion article highlights the existence of these mutations (termed 'mini drivers') and the functional effects that they might have.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Genomic analysis of 551 esophageal adenocarcinomas identifies new driver mutations and biomarkers associated with poor prognosis. More than 50% of esophageal adenocarcinomas contain sensitizing events for CDK4/CDK6 inhibitors, thus providing an evidence base for targeted therapeutics.

The genomic features of precursor conditions of multiple myeloma provide multiple biological insights into disease origins and evolution, together with opportunities to identify those at highest risk of progression.

Here the authors show that transient cell cycle arrest reprograms CD8⁺ T cells into a highly energized state, increasing proliferation and antitumor activity and boosting efficacy of immunotherapies in cancer models.

In a post-hoc analysis of circulating tumor DNA (ctDNA) features from patients with metastatic prostate cancer treated with [¹⁷⁷Lu]Lu–PSMA-617 or cabazitaxel in the randomized phase 2 TheraP trial, low ctDNA levels at baseline were predictive of clinical benefit from [¹⁷⁷Lu]Lu–PSMA-617, and PTEN or ATM alterations were identified as potential biomarkers of response.

The genomic differences between primary and metastatic tumours are assessed across 23 cancer types using pan-cancer whole-genome analysis.

A platform using matched patient-derived lung tumouroids and healthy lung organoids enables accurate examination of patient responses to CAR T therapy and offers a faithful framework for improved CAR T design.

Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.

Whole-genome sequencing of tumours from 560 breast cancer cases provides a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions; several mutational signatures in these cancer genomes are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair.

Chan and colleagues report that tumor ecosystem and microbiome features are associated with response to anti-PD-L1 avelumab plus chemoradiotherapy in patients with locally advanced head and neck cancer.

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, the authors sequence childhood and adult osteosarcomas, identifying mutations in insulin-like growth factor signalling genes and distinct genomic rearrangement profiles characterized by chromothripsis-amplification.

Whole-gene sequencing of microdissected gastric glands from individuals with and without gastric cancer reveals distinct patterns of somatic mutations and provides insights into influences on the somatic evolution of the gastric epithelium.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Explosive growth is attributed to the BCR::ABL1 gene 3–14 years before diagnosis of chronic myeloid leukaemia, highlighting the oncogenic potency of gene fusion and the slow and sequential trajectories of most other cancers.

DNA damage can arise from natural cellular processes, but how cells prevent resulting mutations is unclear. Here, the authors show that the enzyme Polκ protects mouse tissues from mutations caused by endogenous guanine lesions, revealing how DNA repair and damage tolerance pathways cooperate to maintain genome integrity.

A combined modelling and tumour analysis approach is used to study the temporal and spatial patterns of subclone evolution in the TRACERx renal study. Studying the tumour shape and spatial features of clonal diversity in early-stage tumours may allow the prediction of tumour progression and patterns of subclone diversification over time.

Krisai et al. compare brain structure and cognitive function in elderly patients with and without atrial fibrillation using brain MRI and cognitive testing. They find that atrial fibrillation is associated with more brain lesions and lower cognitive function, but the cognitive impairment occurs primarily through direct effects of the arrhythmia rather than through brain damage.

The genomic landscape of diffuse gliomas remains to be characterised. Here, the authors perform whole genome sequencing of 403 tumours and identify recurrent coding and non-coding genetic mutations, their associations with clinical outcomes and potential therapeutic targets.

The GLASS Consortium studies the evolutionary trajectories of 222 patients with a diffuse glioma to aid in our understanding of tumour progression and treatment failure

Uprooting stem cells from their native environment and transplanting them to other individuals exaggerates selective pressures, distorting and accelerating the loss of clonal diversity in contrast to the unperturbed haematopoiesis of donors.

Mucosal melanomas are challenging to treat partly because so little is known about the genetic drivers underpinning them. Here, the authors perform a genomic landscape analysis of samples collected from three continents, revealing a potential role for CDK4/6 or MEK inhibition in the treatment of the disease.

The authors synthesize bee assemblage data from 681 crop fields across three continents, finding that local pesticide hazards and decreasing adjacent semi-natural habitats both negatively affected wild bee abundance and species richness in crop fields, while pesticides also reduced functional diversity.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Mitochondrial respiration provides reducing power to the electron transport chain (ETC), driving proton pumping and ATP synthesis required for T cell activation and differentiation. Here, the authors use alternative oxidase (AOX) as a mechanistic probe to bypass cytochrome c oxidase deficiency and thereby isolate the role of respiration and demonstrate that intact mitochondrial respiration is important for T cell proliferation, effector function, memory formation, and regulation of apoptotic and metabolic signaling pathways.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Haematopoiesis has high clonal diversity up to about 65 years of age, after which diversity drops precipitously owing to positive selection acting on a handful of clones that expand exponentially throughout adulthood.

The genomic landscape of hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) remains to be explored. Here, the authors perform multiomic analysis on 94 tumours from 79 patients and identify the molecular features of metastatic disease and treatment response.